Aminoindan derivatives

ABSTRACT

This invention is directed to compounds of the following formula                    
     wherein when a is O, b is 1 or 2; when a is 1, b is 1, m is from 0-3 X is O or S, Y is halogeno, R 1  is hydrogen C 1-4  alkyl, R 2  is hydrogen, C 1-4  alkyl, or optionally substituted propargyl and R 3  and R 4  are each independently hydrogen, C 1-8  alkyl, C 6-12  aryl, C 6-12  aralkyl each optionally substituted. 
     This invention is also directed to the use of these compounds for treating depression, Attention Deficit Disorder (ADC), Attention Deficit and Hyperactivity Disorder (ADHD), Tourette&#39;s Syndrome, Alzheimer&#39;s Disease and other dementia&#39;s such as senile dementia, dementia of the Parkinson&#39;s type, vascular dementia and Lewy body dementia. 
     This invention is further directed to a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

This application is a continuation of PCT International Application No. PCT/US97/24155, filed Dec. 18, 1997, designating the United States of America, which is claiming priority of Israeli Patent Application Nos. 119853, filed Dec. 18, 1996 and 120510, filed Mar. 24, 1997, the contents of which are hereby incorporated by reference into the present application.

FIELD OF INVENTION

The present invention relates to novel compounds, pharmaceutical compositions containing said compounds and their use in the treatment of various CNS disorders.

BACKGROUND OF THE INVENTION

Dementia exists in several forms including static dementia, Alzheimer's-type dementia, senile dementia, presenile dementia and progressive dementia. One of the common pathological features of several types of dementia is the lack of the neurotransmitter acetylcholine. This has led to the development of acetylcholine esterase inhibitors for use in the treatment of dementias such as the compound tacrine. A summary of the different approaches to and progress made in the treatment of Alzheimer's Disease may be found i Drugs of the Future (1995) 20(11): 1145-1162.

Recently, compounds that in addition to inhibiting acetylcholine esterase, possess inhibitory activity against monoamine oxidase type A (MAC-A) have been developed. The perceived benefit of having the anti-MAO-A activity is stated to be an anti-depressant effect (European Patent Publication Nos. 614,888 and 664.291)

U.S. Pat. Nos. 5, 387,133, 5,453,446, 5,457,133 and 5,519,061 all disclose that the compound (R)-N-propargyl-1-aminoindan, a highly selective monoamine oxidase type B (MAO-B) inhibitor is effective in the treatment of dementias of the Alzheimer type and memory disorders. There is no indication given therein that the compound might have acetylcholine esterase inhibitory activity. Furthermore, the compound is only very weakly active as a MAO-A inhibitor.

PCT International Publication No. WO95/18617 discloses various aminoindan derivatives that are active in a variety of CNS disorders including dementias of the Alzheimer type. There is no indication given therein that any of the compounds disclosed might have acetylcholine esterase inhibitory activity.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

wherein when a is 0; b is 1 or 2; when a is 1, b is 1; m is from 0 to 3; X is O or S; Y is halogeno; R₁ is hydrogen or C₁₋₄ alkyl; R₂ is hydrogen, C₁₋₄ alkyl or optionally substituted propargyl; and R₃ and R₄ are each independently hydrogen, C₁₋₈ alkyl, C₆₋₁₂ aryl, C₆₋₁₂ aralkyl or C₆₋₁ cycloalkyl optionally substituted.

The invention relates to the compounds themselves, pharmaceutical composition containing said compounds and their use in the treatment of depression. Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), Tourette's Syndrome, Alzheimer's Disease and other dementias such as senile dementia, presenile dementia, progressive dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.

A further aspect of the present invention relates to the use of the compounds of formula I in the treatment of neurotraumatic disorder. As used herein the term “neurotraumatic disorder” is meant to include damage caused to the nervous system (both central and peripheral) by virtue of ischemic damage such as that which occurs in stroke, hypoxia or anoxia, neurodegenerative diseases, Parkinson's Disease, Alzheimer's Disease, Huntigton's Disease, neurotoxic injury, head trauma injury, spinal trauma injury, peripheral neuropathy or any form of nerve damage.

An additional aspect of the present invention relates to the use of the compounds of formula I in the treatment of memory disorder or depression.

The present invention relates to the racemic compounds themselves and optically active enantiomers thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compound of formula I:

wherein when a is 0, b is 1 or 2; when a is 1, b is 1, m is from 0-3, X is O or S; Y is halogen; R₁ is hydrogen or C₁₋₄ alkyl; R₂ is hydrogen, C₁₋₄ alkyl, or optionally substituted propargyl, and R₃ and R₃ are each independently hydrogen, C₁₋₅ alkyl, C₆₋₁₂ aryl, C₆₋₁₂ aralkyl or C₆₋₁₂ cycloalkyl each optionally substituted.

In an embodiment of the present invention, a is 0 and b is 1. In another embodiment of the present invention, a is 0, b is 1, and X is O.

In an embodiment of the present invention, X is O. In an additional embodiment of the present invention, X is S.

In an embodiment of the present invention, R₂ is selected from the group consisting of hydrogen, methyl, ethyl or optionally substituted propargyl.

In another embodiment of the present invention, R₂ is propargyl.

In a further embodiment of the present invention, the compound is selected from the group consisting of: (rac) 6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl, (rac) 6-(N,N-dimethyl, carbamyloxy)-N′-methyl-N′-propargyl-1-aminoindan HCl; (rac) 6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminotetralin HCl; (rac)6-(N,N-dimethyl-thiocarbamyloxy)-1-aminoindan HCl; (rac)6-(N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (rac)5-chloro-6-(N-methyl, N-propylcarbamyloxy)-N′-propargyl-1-aminoindan HCl; (S)-6-(N-methyl, N-proyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; and (R)-6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan hemi-(L)-tartrate.

In a further embodiment of the present invention, R₁ is hydrogen, methyl or ethyl and R₂ is hydrogen, methyl, ethyl or optionally substituted propargyl. In a further embodiment of the present invention, the propargyl group is substituted with a C₁₋₄ alkyl group on the methylene group (R₆ in Scheme I).

According to the present invention, the term “halogeno” is used to refer to fluoro, chloro, bromo, or iodo.

In an embodiment of the present invention, when m is greater than 1 each Y may be the same or difference.

In an additional embodiment of the present invention the group OC(X)NR₃R₄ is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon.

In another embodiment of the present invention, at least one of R₃ and R₄ is methyl and the other is hydrogen, methyl, ethyl, propyl, butyl, hexyl, phenyl, benzyl or cyclohexyl.

In the practice of this invention, pharmaceutically acceptable salts include, but are not limited to, the esylate, mesylate, maleate, fumarate, tartrate, hemi-tartarate, hydrochloride, hydrobromide, p-toluenesulfonate, benzoate, acetate, phosphate and sulfate salts.

The subject invention further provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The “therapeutically effective amount” of a compound of formula I or a pharmaceutically acceptable salt thereof may be determined according to methods well known to those skilled in the art, indications of such amounts are given below.

These compositions may be prepared as medicaments to be administered orally, parenterally, rectally, or transdermally.

Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, sublingual tablets, syrups and suspensions. In one embodiment, the pharmaceutically acceptable carrier is a solid and the pharmaceutical composition is a tablet. The therapeutically effective amount may be an amount from about 0.5 mg to about 2000 mg, Preferably from about 1 mg to about 1000 mg.

In an alternative embodiment, the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is an injectable solution. The therapeutically effective amount may be an amount from about 0.5 mg to about 2000 mg, preferably from about 1 mg to about 1000 mg. The volume administered may be an amount between 0.5 and 10 ml.

In a further alternative embodiment, the carrier is a gel and the pharmaceutical composition is a suppository. For parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion. For rectal administration there are provided suppositories with hydrophilic or hydrophobic vehicles. For topical application as ointments and transdermal delivery there are provided suitable delivery system as known in the art. For oral or suppository formulations, 0.5-2000 mg per dosage unit and preferably 1-1000 mg per dosage unit.

These compositions may be used alone to treat the above-listed disorders, or alternatively, for example, in the case of Alzheimer's Disease, they may be used as an adjunct to the conventional treatments such as haloperidol, tacrine or deprenyl.

The invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.

EXAMPLES

Compounds of general formula I may be prepared, as shown in Scheme I, from the corresponding carbamoyl derivatives of aminoindan III by reacting the latter with propargyl compounds bearing an appropriate leaving group at the 3-position, e.g. a halide group, mesylate, tosylate, etc., under basic conditions provided by an inorganic base, e.g. K₂CO₃, NaOH, or an organic base e.g. a tertiary amine, in a polar organic solvent, e.g. CH₃CN, DMF, etc., at 15-40° C. preferably at 20-25° C., for a period of time in the range of 5-48 hours, preferably 20-30 hours. The products, obtained after a suitable work-up and purification, are in the form of free bases. Preferably these are converted into their pharmaceutically acceptable salts, e.g., HCl, mesylate, hemi-tartarate, etc.

As shown in Scheme I, compounds of general formula III may be prepared by Boc deprotection of compounds of general formula IV. In turn, compounds of general formula IV may be prepared by carbamylating a compound of general formula V in a conventional manner, e.g. by reacting the compound of formula V with an appropriate carbamoyl halogenide or by an alkylisocyanate. Finally, compounds of general formula V may be prepared by Boc protection of the appropriate hydroxy amines, by methods known to those skilled in the art, N,N-dialkyl aminoindan derivatives may be prepared as shown on in Scheme I by the direct carbamylation of the corresponding N,N-dialkyl-hydroxy-aminoindan or by alkylation of a compound of formula III.

Although Scheme I shows the preparation of carbamoyl derivatives the same process and description above is relevant to the preparation of the thiocarbamates of the present invention.

Starting Materials 6- and 7-Hydroxy-1-aminoindans may be prepared by demethylation of the respective 6- and 7-methoxy-1-aminoindans. The latter may be obtained from the corresponding 1-indanones, either by their conversion to the oximes, followed by reduction, or by their reductive amination (NaCNBH₃ and NH₄OAc)².

6-Hydroxy aminoindan may also be prepared from aminoindan via a regioselective Friedel—Crafts acylation of a suitably N-protected aminoindan, followed by a Baeyer—Williger oxidation and finally hydrolysis⁵. 6-hydroxy-(R)-1-aminoindan may thus be prepared by the method described in the Example below and Scheme II, wherein “R” is optionally substituted alkyl.

N-Methyl-6-hydroxy-1-aminoindan was prepared by demethylation of 6-methoxy-N-methyl-1-aminoindan, which was prepared from 6-methoxy-1-aminoindan by reductive alkylation (e.g. ethyl formate, followed by LiAlH₄ reduction), or alternatively, by reductive amination (MeNH₂, HCl, NaCNBH₃) of 6-methoxy-1-indanone². N-ethyl-6-hydroxy-1-aminoindan was obtained by acetylation of 6-hydroxy-1-aminoindan (Ac₂O, KOH), followed by reduction (LiAlH₄). N,N-Dimethyl-6-hydroxy-1-aminoindan was prepared by demethylation of the corresponding 6-methoxy analogue, which was prepared by reduction alkylation (formaldehyde, formic acid) of 6-methoxy-1-aminoindan. 4-Hydroxy-1-aminoindan may be prepared from 4-hydroxy indanone by converting the latter to the oxide, followed by reduction¹. 4-Hydroxy indanone may be prepared from dihydrocoumarin.³

7-Hydroxy-1-aminotetralin and 7-hydroxy-2-aminotetralin were prepared by demethylation of the corresponding 7-methoxy analogues. The latter were prepared by reductive amination (as above) of the corresponding 7-methoxy 1- and 2-tetralones.

7-Methoxy-2-tetralone was prepared from 2,7-dimethoxytetralin according to Copinga, et al⁴.

Preparation of 6-Hydroxy-(R)-1-aminoindan (as shown in Scheme II)

N-Trifluoroacetyl-(R)-1-aminoindan

To a cooled (0-5° C.) solution of trifluoroacetic anhydride (194.6 g, 0.926 mol) in toluene (680 ml) was added dropwise a solution of (R)-1-aminoindan (base) (113.3 g 0.85 mol) in toluene (50 ml) and stirred under ice-cooling for 3½ hours. A solution of KOH (67.25 g, 1.2 mol) in water (1000 ml) was then added, under cooling. The reaction mixture was stirred for further 2 hours at room temperature and filtered. The solid was collected by filtration, washed with water (680 ml) and dried in vacuo at 60° C. to give 152 g (78%) of a white solid. mp:153-154° C. The solution was evaporated in vacuum and the crystals were filtered and washed with water. The solid was dried in vacuo at 60° C. The second crop (25 g) was crystallized from a mixture of hexane and ethyl acetate to give 18 g (9%) of a white solid, mp:153-154° C. The total yield was 170 g (87%).

6-Chloroacetyl-N-trifluoroacetyl-(R)-1-aminoindan

To a suspension of AlCl₃ (89.2 g, 0.67 mol) in 1,2-dichloroethane (600 ml) was added chloroacetyl chloride (55.7 ml. 78.9 g, 0.7 mol) dropwise at 0-5° C. under nitrogen for 20 minutes and it was then left to warm up to 20-25° C. To this mixture was added N-trifluoroacetyl-(R)-1-aminoindan (34.4 g, 0.15 mol) for 3 hours at 20-25° C. The resulting mixture was then stirred or an additional 30 minutes and poured into a mixture of ice-cold water (1.5 l) and 1,2-dichloroethane (11). The mixture was stirred for 5 minutes and the layers were separated. The aqueous layer was extracted with 1,2-dichloroethane (2×750 ml). The combined organic layers were washed with water (2×900 ml) and 5% aqueous NaHCO₃ solution (3×900 ml). The organic layer was dried (Na₂SO₄) and the solvent was removed under reduced pressure to give a solid, which was recrystallized from ethanol to give 15 g (48%) of a white solid mp: 166-167° C.

6-Chloroacetoxyl-N-trifluoroacetyl-(R)-1-aminoindan

6-Chloroacetyl-N-trifluoroacetyl-(R)-1-aminoindan (30.57 g, 0.1 mol) was dissolved in anhydrous dichloromethane (210 ml) and 3-chloroperoxybenzoic acid (70%, 44.87 g, 0.26 mol) was added all of once. The suspension was cooled to 0° C. and trifluoroacetic acid (11.4 g, 0.1 mol) was added dropwise for 5-10 minutes. The reaction flask was protected from light and the mixture was stirred for 3-5 days at room temperature. The reaction mixture was poured into water (300 ml.). The mixture was neutralized with ammonium hydroxide solution. The layers were separated. The aqueous layer was extracted with dichloromethane (200 ml). The combined organic layers were dried (Na₂SO₄) and the solvent was removed under reduced pressure to give a solid, which was recrystallized from ethanol to give 15 g (48%) of a white solid mp: 169-170° C.

6-Hydroxy-(R)-1-aminoindan

A suspension of 6-chloroacetoxy-N-trifluoroacetyl-(R)-1-aminoindan (25.4, 0.11 mol) and K₂CO₃ (38.0 g, 0.275 mol) in a mixture of methanol (275 ml) and water (175 ml) was stirred at 70° C. for 1.5 hours. Methanol was removed in vacuo, and the aqueous phase was neutralized with 10% hydrochloric acid. The mixture was filtered and the solid was washed with water. The mother liquor wave evaporated under reduced pressure to a small volume. The suspension was neutralized, filtered and the brown solids were crystallized from methanol (twice) to give 7.0 g (43%) of a white solid mp:200-203° C.

Preparation of the corresponding S-enantiomer may be carried out in the same manner using (S)-1-aminoindan as the starting material.

Resolution of Enantiomers:

The R- and S- enantiomers of each compounds may be obtained by optical resolution of the corresponding racemic mixtures. Such a resolution can be accomplished by any conventional resolution method well known to a person skilled in the art, such as those described in U.S. Pat. No. 4,833,273, issued May 23, 1989 (Goel) and in J. Jacques, A Collet and S. Wilen, “Enantiomers, Racemates and Resolutions,” Wiley, New York (1981). For example, the resolution may be carried out by preparative chromatography on a chiral column. Another example of a suitable resolution method is the formation of diastereomeric salts with a chiral acid such as tartaric, malic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine, followed by recrystallization to isolate the diastereomeric salt of the desired enantiomer.

Alternatively, selected starting materials, intermediates or end products may be resolved into their respective enantiomers by the method described in PCT International Application Publication No. WO/96US/21640, wherein the compound to be resovlent is first converted into its N-benzyl derivative. The N-benzyl derivative is then resolved using either R or S-mandelic acid. The resolved product is converted to its base and reduced under acidic conditions to provide the desired enantiomer. Preferably, the starting material is resolved prior to Boc protection and carbamylation.

The R and S enantiomers of the starting materials may also be prepared from R and S enantiomers of aminoindan via a regioselective Friedel—Crafts acylation of a suitably N-protected optical isomer of aminoindan, followed by a Baeyer-Williger oxidation and finally hydrolysis⁵, thus obviating the need for optical resolution.

References

1. Y. Oshiro, et al, J. Med. Chem. 34: 2004 (1991);

2. R. F. Borch, et al, J. Am. Chem. Soc. 93:, 2897 (1971);

3. J. G. Cannon, et al, J. Med. Chem. 28: 515 (1985);

4. S. C. Copinga, et al, J. Med. Chem. 36: 2891 (1993); and

5. K. Teranishi et al, synthesis 1018 (1994).

Preparation of Compounds of the Invention as shown in Scheme I

A: Boc—protection and carbamylation

1. Boc Protection

6-hydroxy N-Boc aminoindan

A solution of 6-hydroxy aminoindan (16 g, 107 mmol), di-t-butyl dicarbonate (23.8 g, 109.2 mmol) and Et₃N (16.74 ml, 120 mmol) in THF (375 ml) was stirred at room temperature (RT) for 20 hrs. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in CH₂Cl₂ (200 ml), washed with water (200 ml). dried over Na₂SO₄ and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (hexane/EtOAc 2:1) to give 23 g of a solid (86%).

2. Carbamylation

6-(N-Me, N-Et carbamyloxy) N-Boc aminoindan

To a stirred and ice-cooled solution of N-Box 6-hydroxy aminoindan (7.5 g, 30 mmol) in acetonitrile (75 ml) was added N-Me,N-Et carbamoyl chloride (6.3 g, 51.8 mmol), followed by a dropwise addition of NaH (60% in oil, 1.56 g, 39 mmol). The reaction mixture was stirred for 2 hrs at RT under argon. After evaporation of the solvent in-vacuo, water (100 ml) was added, and extracted with ether (3×100 ml). The organic phase was washed with dilute NaOH (pH 10-11), dried and evaporated to dryness in-vacuo. Purification by column chromatography (hexane:EtOAc 2:1) afforded 7.8 g (77%) of an oil.

In this manner the intermediates in Tables 1 and 2 were prepared, in Table 1 and all further Tables the heading “position” refers to the ring position of the carbamyl group unless otherwise indicate.

TABLE 1 N-Boc protected carbamyloxy aminoindans

position Y R1 R3 R4 yield (%) 6- H H Me Me 92 6- H H Me Pr 95 6- H H Me Et 77 7- H H Me Me 92 7- H H Me Et 83 7- H H Me Pr 95 6- H Et Me Me 76 6- H Me Me Me 92 7- H Me Me Me 78 6- H Me Me Pr 80 6- H H Me n-hexyl 98 4- H H Me Me 85 4- H H Me Et 87 6- H H Me Et 89 6- H H Me cyclohexyl 98 6- H H Me p-OMe-phenyl 97 6- H H Me phenyl 93 6- H H Me CH₂-phenyl 83 6- 5-Cl H Me Et 88 6- 5-Cl H Me Pr 97 6- H H Me Bu 99 6- H H Et Bu 93 6- H H Et cyclohexyl 94

TABLE 2 N-Boc protected carbamyloxy aminotetralins

position of amine R1 R3 R4 yield (%) 2- H Me Me 85 2- H Me Et 79 1- H Me Me 85 1- H Me Et 98

B: Boc—Deprotection

6-(N-Me, N-Et Carbamyloxy) aminoindan, HCl (Compound 3)

6-(N-Me, N-Et Carbamyloxy) N-Boc aminoindan (7.8 g, 23.3 mmol) was dissolved in dioxane (80 ml), and a 20% solution of gas. HCl in dioxane (80 ml) was added. After 2 hr stirring at RT the solvent was evaporated in-vacuo and the residue was treated with dry ether (200 ml) and the mixture stirred at RT for 4 hrs and filtered, to give 6.15 g (0.7 mmol, 97%) of 6-(N-Me,N-Et carbamyloxy) aminoindan hydrochloride.

In this manner the following compounds of general formula I as shown in Tables 3, 3a and 4 were prepared. Spectral data relating to these compounds is given in Tables 7, 7a and 8.

TABLE 3 Carbamyloxy aminoindan HCl salts

cryst/slurry yield # position R1, R2 R3 R4 solvent mp(° C.) (%)  1 6- H, H Me Me Et₂O 156-8 93  2 6- H, H Me Pr Et₂O 165-7 27  3 6- H, H Me Et Et₂O 150-2 50  4 7- H, H Me Me Et₂O  156-60 93  5 7- H, H Me Et Et₂O 185-7 55  6 7- H, H Me Pr Et₂O 153-5 33  7 6- H, Et Me Me Et₂O 172-4 91  8 6- H, Me Me Me Et₂O  178-80 88  9 7- H, Me Me Me dioxane  169-71 98 10 6- H, Me Me Et Et₂O 172-4 87 11 6- H, Me Me Pr Et₂O 165-7 98 12 6- Me, Me Me Me Et₂O 164-6 62 13 4- H, H Me Me Et₂O  198-200 90 14 4- H, H Me Et Et₂O 183-5 92 15 6- H, H Me n- dioxane  111-12 78 hexyl  16* 6- H, H Me Et Et₂O 197-8 89 17 6- H, H Me cyclohexyl Et₂O 207-8 86  18** 6- H, H Me Et Et₂O 202-4 84 48 6- H, H H Et MeOH/EtOAc 191-2 74 49 6- H, H H Pr MeOH/EtOAc 171-3 67 50 6- H, H Me p-OMe- iPrOH 225-7 92 Phenyl 51 6- H, H Me CH₂- Et₂O 78 Ph  52* 6- H, H Me Me Et₂O 83  53** 6- H, H Me Me Et₂O 81 88 6- H, H Me Ph Et₂O 96   66*** 6- H, H Me Et Et₂O 116-9 92   67*** 6- H, H Me Pr Et₂O 181-3 86 80 6- H, H Me Bu Et₂O 54 84 6- H, H Et cyclohexyl Et₂O 196-8 89 *R-enantiomer **S-enantiomer ***5-chloro

TABLE 3a Thiocarbamyloxy aminoindan HCl salts

cryst/slurry yield # position R1, R2 R3 R4 solvent mp(° C.) (%) 44 6- H, H Me Me MeOH/EtO 244-5 55 45 6- H, H Me Et MeOH/EtOAc 236-8 58

TABLE 4 Carbamyloxy aminotetralin HCl salts

position of cryst/slurry yield # amine R1 R3 R4 solvent mp(° C.) (%) 19 2- H Me Me ether a) 96 20 2- H Me Et ether a) 95 21 1- H Me Me ether 196-8 99 22 1- H Me Et ether 166-8 85 a): wide melting range; compound is a hemi-hydrate

C: Propargylation and salt formation

The compound prepared in Step B may be optionally propargylated to provide further compounds of general formula I.

6-(N-Me, N-Et carbamyloxy) N-propargyl aminoindan, HCl (Compound 25)

To a stirred mixture of 6-(N-Me, N-Et carbamyloxy) aminoindan. HCl (5.2 g, 19.2 mmol), potassium carbonate (5.31 g, 38.4 mmol) in acetonitrile (250 ml), was added a solution of propargyl bromide (2.06 g, 17.28 mmol) in acetonitrile (10 ml). The reaction mixture was stirred at RT under nitrogen for 25 hrs, and filtered. The filtrate was evaporated to dryness in-vacuo and the residue was purified by column chromatography (EtOAc) to give 3.6 g (13.2 mmol, 69%) of the free base as a yellow oil.

The free base was dissolved in dry ether (150 ml) and HCl/ether (15 ml) was added. The mixture was stirred at RT for 1 hr, filtered and the solid was recrystallized from iPrOH/ether to give 3.5 g (11.3 mmol, 59%) of the title compound as a white solid.

6-(N,N-Dimethylcarbamyloxy)-N-propargyl aminoindan mesylate Compound (24)

To a stirred mixture of 6-(N,N-dimethylcarbamyloxy) aminoindan HCl (1.88 g, 7.33 mmol), K₂CO₃ (2.03 g, 14.66 mmol) and acetonitrile (70 ml) was added a solution of propargyl bromide (0.79 g, 6.6 mmol) in CH₃CN (5 ml) dropwise over 5 min, under nitrogen. The mixture was stirred under N₂ for 24 hrs, filtered and the solvent was removed at reduced pressure. The residue was taken up into water (150 ml) and toluene (150 ml). This mixture was stirred while adjusting the pH of the aqueous layer to 3.75 by the addition of 20% aq. HCl. The aqueous layer was separated and extracted with toluene (2×100 ml) and brought carefully to pH 7.5 by the addition of 10% aq. NaOH solution. It was then extracted with toluene (100 ml+4×70 ml). The combined toluene layers were dried (Na₂SO₄), filtered and the solvent was removed under reduced pressure to give 1.06 g (62%) of a yellow oil.

To a stirred solution of the free base (1.65 g, 6.4 mmol) in anh. ether (60 ml) was added dropwise a solution of methanesulfonic acid (0.7 g, 7.29 mmol) in ether (10 ml). The resulting suspension was stirred at 25° C. for 30 min and then allowed to settle for an additional 30 min. The ether was then decanted off, and the residue was dried under vacuum. It was then recrystallized from iPrOH/ether to give 2.05 g of a white solid (90.3%).

In this manner the following compounds of general formula I as shown in Tables 5, 5a and 6 were prepared. Analytical data relating to these compounds is given in Tables 9, 9a and 10.

TABLE 5 Carbamyloxy-N-propargyl aminoindans

cryst/slurry mp yield # X position R1 R3 R4 solvent (° C.) (%) 23 Cl 6- H Me Me iPrOH/Et₂O 180-2 52 24 mesylate 6- H Me Me iPrOH/Et₂O 147-9 60 25 Cl 6- H Me Et iPrOH/Et₂O 194-6 59 26 Cl 6- H Me Pr iPrOH/Et₂O 183-5 46 27 Cl 7- H Me Me iPrOH/Et₂O  219-20 65 28 Cl 7- H Me Pr iPrOH/Et₂O 185-6 53 29 Cl 6- Me Me Me iPrOH/Et₂O  199-201 55 30 Cl 6- Me Me Et Et₂O 196-8 47 31 Cl 6- Et Me Me iPrOH/Et₂O 212-3 71 32 Cl 7- Me Me Me iPrOH/Et₂O  169-71 63 33 Cl 7- H Me Et iPrOH/Et₂O 208-9 64 34 Cl 4- H Me Me Et₂O 196-8 85 35 Cl 4- H Me Et Et₂O 183-5 85 36 Cl 6- H Me n- iPrOH/Et₂O 106-8 53 hexyl  37* Cl 6- H Me Et Et₂O  159-60 88 38 Cl 6- H Me cyclo Et₂O 174-5 55 hexyl  39** Cl 6- H Me Et Et₂O 160-2 61  54* mesylate 6- H Me Me Et₂O  139-41 54  55** mesylate 6- H Me Me Et₂O  138-40 52 56 Cl 6- H H Et iPrOH/Et₂O 175-7 38 57 Cl 6- H H Pr iPrOH/Et₂O 165-7 48  58* mesylate 6- H Me Et Et₂O  92-4 64  59** mesylate 6- H Me Et iPrOH/Et₂O 72 60 mesylate 6- H Me Et Et₂O 121-3 87 61 Cl 6- H Mr p-OMe- Et₂O 172-4 84 Ph 62 Cl 6- H Me Ph Et₂O 182-4 61 63 Cl 6- H Me CH₂- Et₂O  188-90 58 Ph   64*** Cl 6- H Me Me iPrOH/Et₂O 195-7 55   65*** Cl 6- H Me Et iPrOH/Et₂O  188-90 51   68**** fumarate 6- H Me Et iPrOH 146-8 48  69* fumarate 6- H Me Et iPrOH 115-7 35 70 esylate 6- H Me Et EtOAc  109-11 60   71**** Cl 6- H Me Et Et₂O 161-3 55   72**** Cl 6- H Me Pr Et₂O 164-6 58  73** fumarate 6- H Me Et iPrOH 114-6 81  74** esylate 6- H Me Et EtOAc  95-7 82  75** ½ D-tartrate 6- H Me Et iPrOH 143-5 44  76* ½ L-tartrate 6- H Me Et iPrOH 143-5 41  77* esylate 6- H Me Et EtOAc 106-8 93  78* Cl 6- H Me Pr Et₂O 126-8 89  79* Cl 6- H Me Pr Et₂O 135-7 33 81 Cl 6- H Me Bu Et₂O  168-70 63 83 Cl 6- H Et Bu Et₂O  148-50 42 85 Cl 6- H Et cyclo- Et₂O  178-80 56 hexyl  86* Cl 6- H Me Bu Et₂O  86-8 51  87** Cl 6- H Me Bu Et₂O  88-9 52 *R-enantiomer **S-enantiomer ***substituted propargyl derivatives, R₆ in Scheme I is methyl ****Y: 5-Cl

TABLE 5a Thiocarbamyloxy-N-propargyl aminoindans

cryst/slurry mp yield # X position R1 R3 R4 solvent (° C.) (%) 46 Cl 6- H Me Me Et₂O 152-4 53 47 Cl 6- H Me Et Et₂O 193-5 54

TABLE 6 N-Propargyl aminotetralins

position of cryst/slurry mp yield # amine R1 R3 R4 solvent (° C.) (%) 40 2- H Me Me MeOH/Et₂O 206-8 66 41 2- H Me Et iPrOH/Et₂O 208-9 65 42 1- H Me Me ether 207-9 57 43 1- H Me Et ether 201-3 42

TABLE 7 Analytical Data of Compounds of the Invention shown in Table 3

NMR¹ MS elem. anal. # aryl indan R1, R2 R3, R4 IR (MH⁺) (C, H, N) 1 7.38, 7.20 4.85, 3.10 3.10, 2.96 3446, 2943 221  calc.: 56.14, 6.62, 10.90 7.10 2.96, 2.63 1711, 1487 found: 55.90, 6.67, 10.89 2.14 1393, 1240 2 7.40, 7.21 4.80, 3.10 3.43, 3.27 2970, 2863 249  calc.: 59.05, 7.38, 9.84 7.10 2.95, 2.65 3.10, 2.95 1735, 1608 found: 58.75, 7.33, 9.86 2.15 1.70, 1.63 1396, 1241 0.94, 0.90 2a 7.40, 7.21 4.80, 3.10 3.43, 3.27 249  calc.: 57.23, 7.55, 9.54 (½ 7.10 2.95, 2.65 3.10, 2.95 found: 57.54, 7.29, 9.45 H₂O) 2.15 1.70, 1.63 0.94, 0.90 4 7.47, 7.36 4.91, 3.25 3.18, 3.03 2950, 1701 7.09 3.07, 2.60 1504, 1396 2.25 1234, 1177 5 7.44, 7.29 4.88, 3.20 3.55, 3.39 3446, 2920 235  calc.: 57.70, 7.25, 10.35 7.02 3.14, 2.55 3.14, 2.99 1710, 1472 found: 57.38, 6.97, 10.32 2.23 1.26, 1.18 1403, 1235 6 7.45, 7.30 4.86, 3.20 3.50, 3.32 3448, 2923 249  calc.: 59.05, 7.43, 9.84 7.02 3.04, 2.55 3.13, 2.98 1710, 1485 found: 58.78, 7.47, 9.91 2.23 1.70, 1.63 1226, 1154 0.94, 0.90 7 7.45, 7.29 4.83, 3.17 3.20, 1.33 3.15, 3.0 2948, 2766 249  calc.: 59.05, 7.38, 9.84 7.17 3.02, 2.65 2680, 1725 found: 57.75, 7.40, 9.65 1485, 1386 8 7.43, 7.27 4.75, 3.14 2.73 3.13, 2.97 2950, 2722 235  calc.: 57.70, 7.02, 10.35 7.17 3.03, 2.60 1720, 1390 found: 56.83, 7.09, 10.27 2.30 1160 9 7.52, 7.37 4.83, 3.27 2.74 3.19, 3.04 2963, 2710 235  calc.: 57.70, 7.02, 10.35 7.10 3.10, 2.55 1715, 1579 found: 57.46, 6.73, 10.36 2.38 1472, 1389 10 7.44, 7.25 4.80, 3.15 2.74 3.55, 3.35 2950, 2705  calc.: 59.08, 7.38, 9.84 7.15 3.03, 2.62 3.12, 2.98 1720, 1450 found: 58.74, 7.51, 9.72 2.30 1.25, 1.18 1402 11 7.42, 7.25 4.75, 3.15 2.72 3.45, 3.30 2963, 2723  calc.: 60.33, 7.70, 9.38 7.14 3.10, 2.60 3.10, 2.95 1715, 1465 found: 60.32, 7.75, 9.42 2.28 1.65, 094 1404, 1234 0.88 12 7.43, 7.27 4.96, 3.12 2.75 3.10, 2.96 3480, 1718 249  calc.: 59.05, 7.38, 9.84 7.17 3.05, 2.55 1475, 1390 found: 58.75, 7.41, 9.84 2.42 1237, 1174 13″ 7.53, 7.29 4.71, 2.95, 8.75 3.04, 2.9 221 7.08 2.74, 2.45, 2.0 14″ 7.53, 7.3, 4.71, 2.95, 8.7 3.41, 3.3, 235 7.08 2.73, 2.48, 3/01, 2.89, 2.0 1.18, 1.07 15 7.35, 7.23 4.83, 3.3 3.1,  3.06 2930, 1720 291  calc.: 62.47, 8.33, 8.57 7.01 2.6,  2.16 2.95, 2.91 1471, 1405 found: 62.54, 8.30, 8.61 1.6,  1.29 1248 0.85 16 7.42, 7.22 4.87, 3.16 3.53, 3.39 235 7.12 3.01, 2.65 3.92, 2.99 2.17 1.26, 1.17 17 7.42, 7.22 4.87, 3.15 4.10, 3.85 289  calc.: 62.85, 7.76, 8.63 7.11 2.95, 2.65 3.00, 2.85 found: 62.55, 7.81, 8.33 2.19 1.90-1.40 1.34, 1.13 3 7.43, 7.20 4.86, 3.15 3.51, 3.38 235  calc.: 55.70, 7.25, 10.35 7.12 3.02, 2.64 3.10, 2.95 found: 57.44, 7.06, 10.38 2.18 1.25, 1.15 18 7.43, 7.20 4.86, 3.15 3.51, 3.38 235  calc.: 55.70, 7.25, 10.35 7.12 3.02, 2.64 3.10, 2.95 found: 57.44, 7.06, 10.38 2.18 1.25, 1.15 48 7.41, 7.24 4.87, 3.13 3.23, 1.17 221  calc.: 56.13, 6.68, 10.91 7.13 3.0,  2.65 found: 56.00, 6.66, 10.81 2.17 49 7.41, 7.24 4.87, 3.12 3.17, 1.56 235  calc.: 57.67, 7.07, 10.35 7.13 2.98, 2.65 0.94 found: 57.32, 7.13, 10.31 2.17 50 7.37, 7.16 4.80, 3.10 7.40-7.0  calc.: 61.98, 6.02, 8.03 7.03 2.96, 2.61 3.82, 3.43 found: 61.16, 6.07, 7.77 2.15 3.29 66 7.57, 7.39 4.91, 3.18 3.61, 3.43 269  calc.: 50.41, 6.02, 9.05 3.05, 2.71, 3.20, 3.03 271 found: 50.46, 6.11, 8.77 2.25 1.33, 1.23 67 7.55, 7.36 4.89, 3.14 3.52, 3.36 283  calc.: 52.67, 6.32, 8.78 3.02, 2.68 3.18, 3.02 285 found: 52.67, 6.28, 8.48 2.20 1.77, 1.67 0.99, 0.93 ¹D₂O, unless otherwise specified ″DMSO-d₆

TABLE 7a Analytical Data of Compounds of the Invention shown in Table 3a

NMR (D₂O) MS elem. anal. # aryl indan R1, R2 R3, R4 IR (MH⁺) (C, H, N, S) 44 7.45. 7.20, 4.87, 3.15, 3.44, 3.36 2933, 1714,  calc.: 52.83,  628, 10.27, 11.75 7.11 3.05, 2.65, 1599, 1536, found: 51.11, 6.48, 10.23, 12.16 2.20 1488, 1392 45 7.45, 7.20, 4.75, 3.10, 3.88, 3.79, 2934, 1719,  calc.: 51.22, 6.94, 9.19, 10.52 7.11 2.97, 2.65, 3.39, 3.32, 1594, 1522, found: 51.04, 7.30, 9.31, 11.24 2.20 1.28, 1.25 1497, 1402

TABLE 8 Analytical Data of Compounds of the Invention shown in Table 4

NMR² MS elem. anal. # aryl cyclohex. R1, R2 R3, R4 IR (MH⁺) (C, H, N) 19 7.22, 6.95 3.69, 3.22 3.12, 2.97 3484, 2930 235 calc: 55.81, 7.20, 10.02 (½ 2.93, 2.87 2362, 1699 found: 55.29, 6.93, 9.71 H₂O) 2.22, 1.92 1612, 1500 1391 20 7.20, 6.94 3.70, 3.19 3.48, 3.35 249 calc: 57.23, 7.55, 9.54 (½ 2.90, 2.23 3.08, 2.94 found: 57.50, 7.53, 9.54 H₂O) 1.90 1.20, 1.12 21 7.28, 7.11, 4.56, 2.87 3.10, 2.96 235 calc: 57.70, 7.02, 10.35 7.06 2.77, 2.16 found: 56.97, 6.93, 10.06 2.05, 1.88 22 7.29, 7.13 4.57, 2.88 3.52, 3.37 249 calc: 59.05, 7.38, 9.84 7.07 2.79, 2.15 3.10, 2.97 found: 58.91, 7.18, 9.99 2.05, 1.90 1.25, 1.17 ²D₂O, unless otherwise specified

TABLE 9 Analytical Data of Compounds of the Invention shown in Table 5

NMR³ MS elem. anal. # aryl indan R1 proparg R3, R4 IR (MH⁺) (C, H, N) 23 7.46, 7.30 5.01, 3.20 4.0, 3.16 3.15, 3.0 259 calc.: 61.12, 6.50, 9.51 7.18 3.15, 2.65 found: 60.93, 6.38, 9.47 2.36 24 7.46, 7.30 5.01, 3.20 4.0, 3.16 3.15, 3.0 1711, 1482, 259 calc.: 54.22, 6.26, 7.91 7.18 3.15, 2.65 1439, 1394, found: 53.92, 6.28, 7.84 2.36 1192, 1170 25 7.42, 7.27 4.97, 3.16, 3.97, 3.02 3.52, 3.36 1728, 1435, 273 calc.: 62.23, 6.86, 9.57 7.15 3.0, 2.62, 3.10, 2.97, 1403, 1242, found: 62.42, 6.84, 8.94 2.32 1.24, 1.15 1166 25^(ii) 7.50, 7.32 4.78, 3.10 3.91, 3.74 3.43, 3.32 1728, 1435, 273 calc.: 62.23, 6.86, 9.57 7.10 2.85, 2.45 3.03, 2.90 1403, 1242, found: 62.42, 6.84, 8.94 2.28 1.20, 1.00 1166 26 7.45, 7.30 5.0, 3.16 4.0, 3.03 3.48, 3.32 1725, 1465, 287 calc.: 63.25, 7.18, 8.68 7.17 3.04, 2.65 3.12, 2.98 1429, 1403, found: 63.13, 7.28, 8.93 2.33 1.72, 1.63 1232, 1165 0.96, 0.92 27 7.52, 7.38 5.05, 3.26 3.99, 3.21 3.12, 3.03 3200, 1722, 259 calc.: 61.12, 6.50, 9.51 7.10 3.07, 2.56 1567, 1434, found: 61.01, 6.46, 9.64 2.40 1408, 1238 28 7.52, 7.37 5.02, 3.27 3.98, 3.10 3.65, 3.42 3200, 1727, 287 calc.: 63.25, 7.18, 8.68 7.07 3.09, 2.55 3.18, 3.02 1566, 1468, found: 63.06, 7.30, 8.37 2.38 1.75, 0.98 1438, 1406, 0.93 1222 29 7.44, 7.30 5.20, 3.15 2.80 4.01, 3.13 3.12, 2.97 1729, 1388, 273 calc.: 62.33, 6.80, 9.07 7.19 3.03, 2.57, 1234, 1165 found: 61.97, 6.80, 8.78 2.44 31 7.48, 7.30 5.34, 3.20 3.36, 4.05, 3.12 3.16, 3.01 3180, 1723, 287 calc.: 63.25, 7.18, 8.68 7.23 3.08, 2.65 1.37 1490, 1440, found: 63.42, 7.09, 8.71 2.50 1389, 1230, 1160 32 7.56, 7.39 5.30, 3.28 2.78 4.12, 3.23 3.20, 3.02 1712, 1472, 273 calc.: 62.23, 6.86, 9.07 7.15 3.09, 2.55 1392, 1238, found: 62.05, 6.81, 8.87 1171 33 7.46, 7.32, 4.96, 2.50 3.92, 3.04 3.13, 2.96 1719, 1426, 273 calc.: 62.23, 6.86, 9.07 7.03 2.33 1.24, 1.15 1404, 1233, found: 62.19, 6.77, 9.08 1154 34 7.48, 7.23 5.07, 3.08 4.05, 3.07 3.29, 3.03 3238, 2907 259 calc.: 2.95, 2.65 2769, 2635 found: 2.35 1714, 1470 1392, 1240 35 7.48, 7.23 5.07, 3.08 4.05, 3.07 3.56, 3.41 3197, 2934 273 calc.: 2.95, 2.65 3.15, 3.01 2565, 2431 found: 2.35 1.29, 1.21 1707, 1445 1403, 1236 36 7.45, 7.28 4.98, 3.16 3.98, 3.04 3.49, 3.35 calc.: 65.83, 8.01, 7.68 7.15 3.03, 2.63 3.11, 2.97 found: 65.65, 8.11, 7.82 2.33 1.66, 1.33 0.88 37 7.44, 7.29 4.98, 3.15 3.98, 3.03 3.53, 3.38 3275, 2754 273 calc.: 62.23, 6.86, 9.07 7.18 3.01, 2.63 3.12, 2.98 1719, 1445 found: 62.30, 6.94, 9.09 2.31 1.25, 1.16 1395, 1303 38 7.44, 7.27 4.98, 3.14 3.98, 3.04 4.09, 3.85 3227, 2936 327 calc.: 66.19, 7.50, 7.72 7.16 3.00, 2.64 3.01, 2.88 2612, 2128 found: 65.90, 7.63, 7.55 2.33 1.90-1.45 1711, 1584 1.35, 1.14 1440, 1401 39 7.46, 7.30 4.97, 3.17 3.97, 3.03 3.54, 3.39 3275, 2933 273 calc. 62.23, 6.86, 9.07 7.19 3.04, 2.64 3.13, 3.0 2758, 1720 found: 62.27, 6.95, 9.03 2.32 1.27, 1.19 1445, 1396 1303 54 7.46, 7.30 5.00, 3.17 3.99, 3.05 3.15, 3.0 1711, 1482 259 calc.: 54.17, 6.20, 7.90 7.19 3.05, 2.64 1438, 1395 found: 54.18, 6.27, 7.78 2.33 1192, 1169 55 7.46, 7.30 5.00, 3.17 3.99, 3.05 3.15, 3.0 1711, 1482 259 calc.: 54.17, 6.20, 7.90 7.19 3.05, 2.64 1438, 1395 found: 54.07, 6.25, 7.88 2.33 1192, 1169 56 7.46, 7.32 4.99, 3.17 3.99, 3.05 3.27, 1.20 259 calc.: 61.12, 6.50, 9.51 7.20 3.04, 2.65 found: 60.87, 6.47, 9.34 2.33 57 7.47, 7.32 4.99, 3.18 3.99, 3.06 3.20, 1.61 273 calc.: 62.23, 6.86, 9.07 7.20 3.05, 2.65 0.98 found: 61.60, 6.93, 9.04 2.34 58 7.47, 7.32 5.01, 3.20 4.01, 3.07 3.56, 3.41 273 calc.: 55.43, 6.52, 7.60 7.22 3.08, 2.67 3.14, 3.01 found: 55.08, 6.52, 7.31 2.36 1.29, 1.21 59 7.47, 7.32 5.01, 3.20 4.01, 3.07 3.56, 3.41 273 calc.: 7.22 3.08, 2.67 3.14, 3.01 found: 2.36 1.29, 1.21 60 7.47, 7.32 5.01, 3.20 4.01, 3.07 3.56, 3.41 273 calc.: 55.43, 6.52, 7.60 7.22 3.08, 2.67 3.14, 3.01 found: 55.21, 6.64, 7.40 2.36 1.29, 1.21 61 7.40-7.0 4.96, 3.10 3.96, 3.90 7.40-7.0 351 calc.: 65.20, 5.95, 7.24 2.97, 2.57 3.03 3.81 found: 64.72, 6.04, 6.81 2.30 62 7.60-7.10 4.96, 3.15 3.98, 3.07 7.60-7.10 321 calc.: 67.32, 5.89, 7.85 3.00, 2.61 3.42 found: 67.22, 6.00, 7.54 2.34 63 7.55-7.10 4.97, 3.17, 3.99, 3.07 7.55-7.10 335 calc.: 67.47, 6.20, 7.55 3.00, 2.64, 4.73, 4.59 found: 67.75, 6.32, 7.47 2.36, 2.36 3.14, 3.05 64 7.48, 7.35 5.16, 5.12 4.44, 4.27 3.17, 3.03 273 calc. 62.23, 6.86, 9.07 7.21 3.20, 3.05 3.17, 1.68 found: 62.22, 6.86, 8.96 2.70, 2.35 1.63 65 7.44, 7.36, 5.15, 5.09 4.43, 4.25 3.55, 3.39 calc.: 63.25, 7.18, 8.68 7.27, 7.19 3.20, 3.02 3.25, 3.17 3.13, 3.00 found: 63.15, 7.15, 8.31 2.65, 2.32 1.67, 1.61 1.27, 1.19 71 7.60, 7.44 5.02, 3.20, 4.02, 3.07 3.60, 3.43, 307 calc.: 55.98, 5.87, 8.16 3.06, 2.68, 3.20, 3.02, 309 found: 55.72, 5.88, 8.11 2.36 1.33, 1.23 72 7.59, 7.44 5.01, 3.20, 4.03, 3.07 3.53, 3.36, 321 calc.: 57.15, 6.21, 7.84 3.06, 2.68, 3.20, 3.02, 323 found: 57.05, 6.21, 7.81 2.38 1.79, 1.68, 1.01, 0.95 76 7.47, 7.31, 5.00, 3.20, 4.00, 3.07 3.56, 3.40, 3286, 2972, 273 calc.: 62.17, 6.62, 8.05 7.20 3.06, 2.66, 3.16, 3.00, 1724, 1637, found: 62.31, 6.66, 7.94 2.35 1.28, 1.20 1400, 1308, 1233 81 7.48, 7.31, 5.00, 3.20, 4.01, 3.07 3.53, 3.38, calc.: 64.19, 7.42, 8.32 7.20 3.07, 2.66, 3.14, 3.01, found: 63.99, 7.42, 8.04 2.35 1.65, 1.39, 0.97 83 7.47, 7.31, 5.00, 3.19, 4.01, 3.07 3.52, 3.38, 315 calc.: 65.04, 7.70, 7.98 7.19 3.04, 2.66, 1.68, 1.40, found: 64.75, 7.72, 7.94 2.34 1.29, 1.22, 0.98 85 7.47, 7.31, 5.00, 3.19, 4.01, 3.07, 3.84, 3.42 341 calc.: 66.33, 7.70, 7.43 7.19 3.02, 2.63, 1.85, 1.66, found: 66.75, 7.69, 7.36 2.34 1.23 ³D₂O, unless specified otherwise ^(ii): DMSO-d₆

TABLE 9a Analytical Data of Compounds of the Invention shown in Table 5a

NMR (D₂O) MS elem. anal. # aryl indan propargyl R3, R4 IR (MH⁺) (C, H, N, S) 46 7.48, 7.29, 5.02, 3.19, 4.0, 3.07 3.46, 3.41 calc.: 57.97, 6.11, 9.01, 10.30 7.18 3.05, 2.67, found: 58.07, 6.06, 8.85, 10.23 2.37 47 7.50, 7.31 5.04, 3.21, 4.20, 3.09 3.95, 3.87 calc.: 59.16, 6.47, 8.62, 9.86 7.19 3.07, 2.70, 3.45, 3.38 found: 59.23, 6.39, 8.52, 9.76 2.38 1.35, 1.32

TABLE 10 Analytical Data of Compounds of the Invention shown in Table 6

NMR⁴ MS elem. anal. # aryl cyclohex. R1 proparg R3, R4 IR (MH⁺) (C, H, N) 40 calc: found: 41 7.22, 6.95 3.79, 3.26 4.06, 3.01 3.50, 3.36 3227, 2938 287 calc: 63.25, 7.18, 8.68 2.95, 2.32 3.09, 2.96 2768, 1713 found: 63.16, 6.93, 8.69 1.91 1.24, 1.16 1587, 1474 1394, 1301 42 7.21, 7.03 4.60, 2.81 3.88, 2.95 3.01, 2.87 3234, 2936 273 calc: 62.23, 6.80, 9.07 2.72, 2.15 2774, 2130 found: 62.20, 7.01, 9.3 2.02, 1.84 1732, 1497 1.80 1390 43 7.32, 7.12 4.65, 2.88 3.99, 3.04 3.51, 3.37 3216, 2933 287 calc: 63.06, 7.41, 8.65 2.80, 2.20 3.10, 2.96 2768, 2663 found: 63.2, 7.14, 8.81 2.12, 1.94 1.23, 1.16 2129, 1723 1.85 1425, 1399 ⁴D₂O, unless specified otherwise

BIOLOGICAL EXAMPLES Example 1 Acetylcholinesterase Inhibition in Mice

1.1 In vitro measurement of Acetylcholinesterase (AChE) Inhibition

Human erythrocyte acetylcholinesterase (type XIII, Sigma Israel), was prepared in a stock solution of 1 U/ml, containing Triton (1%) and bovine serum albumin (0.05%) in phosphate buffer (pH 8). The enzyme (0.05 U) was incubated with 3-5 different concentrations of test compound (in triplicate) for periods of from 15 to 60 minutes at 37° C. The substrate acetylthiocholine (0.075 M) and 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB, 0.01 M) were then added and the rate of hydrolysis of the substrate which yields a yellow product monitored spectrophotomerically at 412 nM (Ellman et al., Biochem Pharmacol. (1961) 7: 88-95). The percentage inhibition of AChE by each concentration of drug is calculated by comparison with that of enzyme in the absence of drug. The concentration of each drug that inhibits AChE by 50% (IC₅₀) at the time of peak activity was calculated and is given in Table 11 below.

1.2 Ex vivo measurement of Acetylcholinesterase (AChE) Inhibition

Test drugs or saline were administered sub-cutaneously to male mice (Sabra strain, 28-35 g). At least 4-5 mice were used per dose and a minimum of 3 doses per drug were tested. The mice were sacrificed 15, 30, 60, 70, 90, 120 or 180 minutes after drug administration, the brains rapidly removed (minus cerebellum), weighed and homogenized in 0.1M phosphate buffer, pH 8.0, containing Triton (1 mg/100 g tissue) and centrifuged to remove cell debris. Aliquots (25 μl) of the supernatant were then incubated with acetylthiocholine and DTNB. AChE activity was measured as described above. The % inhibition of whole brain AChE by each dose of drug was calculated by comparison with enzyme activity from 3 saline treated control mice run at the same time. The dose of each drug that inhibits AChE by 50% at the peak of activity (ED₅₀) was calculated and is given in Table 11.

1.3 Acute Toxicity in Mice

Drugs were administered sub-cutaneously in at least 3 doses, to a minimum of 10 mice per dose. The dose that was lethal to 50% of the mice (LD₅₀) within 6 hours after administration was calculated for each drug and is given in Table 11. Therapeutic Ratio was calculated as LD₅₀ divided by ED₅₀ of ex vivo acetylcholine esterase inhibition.

Example 2

2.1 Inhibition of MAO activity in vitro

The MAO enzyme source was a homogenate of rat brain in 0.3M sucrose, which was centrifuged at 600 g for 15 minutes. The supernatant was diluted appropriately in 0.05M phosphate buffer, and pre-incubated with serial dilutions of test compounds for 20 minutes at 37° C. ¹⁴C-Labeled substrates (2-phenylethylamine, hereinafter PEA; 5-hydroxytryptamine, hereinafter 5-HT) were then added, and the incubation continued for a further 20 minutes (PEA), or 30-45 minutes (5-HT). Substrate concentrations used were 50 μM (PEA) and 1 mM (5-HT). In the case of PEA, enzyme concentration was chosen so that not more than 10% of the substrate was metabolized during the course of the reaction. Deaminated products were extracted into toluene-ethyl acetate (1:1 v/v) containing 0.6% (w/v) 2,5-diphenyloxazole (ppo) prior to determination by liquid scintillation counting. Radioactivity in the eluate indicates the production of neutral and acidic metabolites formed as a result of MAO activity. Activity of MAO in the sample was expressed as a percentage of control activity in the absence of inhibitors after subtraction of appropriate blank values. The activity determined using PEA as substrate is referred to as MAO-B, and that determined using 5-HT as MAO-A.

Concentrations of inhibitor producing 50% inhibition of substrate metabolism (IC₅₀) were calculated from the inhibition curves, and are shown in Table 11.

2.2 Inhibition of MAO activity ex vivo

Male Sabra mice, weighing 45-50 g were injected with test compound solutions (prepared in 0.9% saline). Each dose was administered to two or three mice. The mice were sacrificed two hours after drug administration or at a time corresponding to the peak AChE inhibition time (see Table 11). The brain and liver were rapidly dissected and stored in appropriate vials on ice. The tissues were weighed, diluted to {fraction (1/20)} in sucrose 0.3M and stored at −20° C. before performance of the MAO assay described above. The results given in Table 11 relate to measurements made on brain tissue only.

2.3 Inhibition of MAO activity following sub-acute administration to rats

Experiments were done in Sprague Dawley male rats. Procedures were repeated as described in Examples 2.1 and 2.2, but drug administration was continued daily for 14 days. At the end of this period animals were sacrificed and MAO levels determined in the brain, liver and intestines. Compounds 24, 25, 37 and 39 were administered sub-cutaneously and/or per os at a dose of 6 mg/kg(sc) and 10 mg/kg(po) (compound 24), 25 and 50 mg/kg (compound 25), 45 mg/kg (compound 37) and 40 mg/kg (compound 39). The results are shown in Table 11a from which it can be seen that these compounds displayed selectivity in inhibiting MAO enzyme sub-types in the brain in preference to the periphery.

TABLE 11 AChE Inhibition Time Ex vivo to return to MAO-B Inhibition MAO-A Inhibition Acute Toxicity ED50 to peak 50% of Ex vivo Ex vivo LD50 Therapeutic in vitro μmoles/kg activity peak In vitro ED50 In vitro ED50 μmoles/kg Ratio # IC50 μM (AC) t(min) t(min) IC50 μM μmoles/kg IC50 μM μmoles/kg (LD) LD/AC 1 0.6 5.0 30 >120 >1000 >>80 75 >>80 83.8 16.8 23 3.5 22.4 15 70 600 100 800 >120 255 11.4 2 7.3 NT >1000 32 3 20.0 46.3 60-90 >180 >1000 12.6 950 20.6 25 53.0 140.0 60 >180 >1000 200 270 >>350 1400 10.8 26 17.0 120 30-60 264 333 114 >>440 1200 9 27 5.72 30 15 >60 >1000 >>160 >1000 >>160 300 10 28 100.0 NT 5 11.5 85.0 60 >120 >>277 >>277 840 9.9 7 32.0 NT >1000 600 8 1.0 10.0 15-30 >60 >1000 >>50 50 >>50 87 8.7 9 0.18 1.9 15 93 4.9 29 8.5 53.7 15 >60 40 30 40 50 500 9.3 10 38.0 34.7 60-90 >180 >1000 >175 22 >175 740 21.3 30 1300.0 NT 31 10.0 110 >1000 >100 >1000 >100 32 3.7 7.8 15 500 >>20 190 >>20 68 9.0 12 2.0 8.0 15 >1000 130 <20 <2.5 33 540.0 NT >1000 1000 >1000 >>1200 34 0.046 0.65 30 100 0.5 3.7 5.7 35 2.2 10 60 100 <1 33 3.3 37 51 125 500 200 750 >200 1700 13.6 39 36 80 30-60 >180 1000 >>200 550 >>200 1150 14.4 24 3 16.6 15 750 100 850 >120 179 10.8 60 42 58 51 >1000 300 54 1.8 >100 >100 55 2 >100 >100 56 11.5 180 57 2.4 70 25 69 48 10 49 2 17 4 16 9 50 0.26 61 0.75 47 500 >100 700 >100 64 1.9 13.2 >1000 >120 1000 >120 150 11.4 38 33 >1000 10 >400 170 >400 36 15 >400 >1000 >100 >1000 >100 >1000 62 0.57 290 60 100 >>200 80 >>200 63 2.5 140 60-90 120 >300 40 >300 1300 9.3 71 29 >100 130 >100 72 38 >200 >100 >100 78 10 101 60-90 >120 450 >>450 1300 12.9 79 9.4 94 90 >180 >>450 >>450 1000 10.6 81 11.5 40 90 >120 >>100 >>100 920 23 83 80 86 10.5 87 9.1 85 17 >100

TABLE 11a Effect of Compounds 24, 25, 37 and 39 on MAO activity after chronic sub - acutetreatment to rats % MAO-A inhibition % MAO-B inhibition 24 Compound 6(sc) 25 37 39 24 25 37 39 Dose (mg/kg) 10(po) 25 50 45 40 25 25 50 45 40 Brain sc 30 53 75 78 17 50 61 85 87 27 po 0 70 67 20 80 82 Intestine sc 0 0 30 0 0 0 29 45 26 40 po 30 25 0 20 30 21 Liver sc 0 0 10 0 0 0 14 40 29 0 po 10 25 28 0 35 28

Example 3 Effect of drug treatment following closed head injury (CHI) in mice

The procedure for closed head injury followed was as described for rats in Shohami, et al. (J Neurotrauma (1993) 10(2): 109-119) with changes as described.

Animals: Male Sabra mice (Hebrew University strain) weighing 34-40 g were used. They were housed in groups of 10 per cage, in a 12 hr:12 hr light:dark cycle. Food and water were provided ad libitium.

Trauma was induced under ether anesthesia. A longitudinal incision was performed in the skin covering the skull and the skin retracted to expose the skull. The head was fixed manually at the lower plane of the impact apparatus. A weight of 333 g was delivered by an electric device from a distance of 3 cm to the left hemisphere, 1-2 mm lateral to the midline in the midcoronal plane. Test compounds were injected sub-cutaneously at a dosage corresponding to the ED₅₀ acetylcholinesterase, once 15 min. after CHI.

3.1 Assessment of Motor Function.

Motor function and reflexes were evaluated in the injured mice at different times after closed head injury (CHI) using a neurological severity score (NSS) as shown in Table 12 below, which is modified from that described for rats (Shohami, et al. supra.). One point was awarded for the lack of a tested reflex or for the inability to perform the tasks outline in the Table. The maximal score that can be reached at 1 hour post-CHI is 25 points and 21 at later times. The difference in NSS at 1 hr and at any other time reflects the recover, and is referred to as ΔNSS. An NSS score of 15-19 at 1 hr denotes severe injury, 11-14 moderate injury and less than 10 mild injury. The NSS recorded after treatment with test compound or control is shown in Table 13.

TABLE 12 Neurological Severity Score for mice after Closed Head Injury. Points at Points at any Parameter 1 hour other time Inability to exit from a circle (30 cm diameter) when left in its center for 30 min 1 for 60 min 1 for >60 min 1 1 Loss of righting reflex for 10 second 1 for 20 seconds 1 for >30 seconds 1 1 Hemiplegia - inability of mouse to resist 1 1 forced changes in position Flexion of hind limb when lifted by tail 1 1 Inability to walk straight when placed on 1 1 the floor Reflexes Pinna reflex 1 1 Corneal reflex 1 1 Startle reflex 1 1 Clinical grade Loss of seeking behavior 1 1 Prostration 1 1 Loss of reflexes Left forelimb 1 1 Right forelimb 1 1 Left hindlimb 1 1 Right hindlimb 1 1 Functional test Failure in beam balancing task (0.5 cm wide) for 20 seconds 1 1 for 40 seconds 1 1 for >60 seconds 1 1 Failure in round stick balancing task (0.5 cm in diameter for 10 seconds 1 1 Failure in beam walking task 3 cm wide 1 1 2 cm wide 1 1 1 cm wide 1 1 Maximum Points 25 21

Results Assessment of Motor Function

TABLE 13 Change in Neurological Severity Score after Closed Head Injury in Mice ΔNSS, 24 hr ΔNSS, 7 days ΔNSS, 14 days Drug/dose N post-CHI post-CHI post-CHI Saline, 1 ml/kg 51 4.75 ± 0.17 5.83 ± 0.36 5.96 ± 0.4  1 (1.3 mg/kg) 10 5.50 ± 0.34* 7.31 ± 0.42* 9.21 ± 0.47 24 (6.5 mg/kg) 12 6.11 ± 0.23* 8.67 ± 0.41* 9.67 ± 0.66* 25 (46 mg/kg) 10 5.00 ± 0.42 7.42 ± 0.62* 9.01 ± 0.69* 25¹ (46 mg/kg) 10 4.90 ± 0.43 7.70 ± 0.33* 8.80 ± 0.33* 10 (15 mg/kg) 11 5.36 ± 0.39 6.64 ± 0.41* 6.73 ± 0.52 37 (30 mg kg) 12 5.50 ± 0.26 6.92 ± 0.38 8.25 ± 0.62 39 (30 mg/kg) 14 5.36 ± 0.25 6.71 ± 0.45 7.64 ± 0.48 ¹administered 60 min before CHI *significantly different from saline control (p < 0.05)

3.2 Assessment of Reference Memory

Morris Water Maze Test: the water maze consists of a circular aluminum pool, 1 m in diameter and 60 cm in depth, filled with water to a depth of 17.5 cm. The hidden goal platform is a glass vessel (15 cm diameter×16.5 cm height) placed upside down at a fixed location in the pool, 1 cm below the surface of the water. The water temperature is maintained at 24° C. and the pool is always placed in the same position in the room to provide the same extra-maze cues. Prior to CHI (as described in Example 3 above), mice were given 3 trials per day for 5 consecutive days to establish a baseline performance—measured as the latency to find the platform from the same start location. Commencing 24 hr after CHI, mice were retested daily for 2 weeks in 3 trials per day.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1, 2 and 3 show the reduction in latency for mice treated with compounds 24 (6.5 mg/kg), 25 (46 mg/kg), 1 (1.3 mg/kg), 10 (15 mg/kg), 37 (30 mg/kg) or 39 (30 mg/kg) compared to saline treated controls after CHI. It appears that immediately post-CHI mice forget the location of the goal. Memory is enhanced following treatment with test compounds, as compared to saline treated mice. In the Figures the arrow shows the time of CHI.

Example 4 Effect On Mice Having Experienced A Hypobaric Hypoxic Episode

The hypobaric hypoxic model is a well accepted model for assessing the activity of compounds believed to possess neuroprotective activity. The model is based on that described in Nakanishi, M., et al. Life Sci. (1973) 13: 467, Oshiro, et al., J. Med. Chem. (1991) 34: 2004-2013 and U.S. Pat. No. 4,788,130.

A 12 liter desiccator (desiccator A) and a 2.5 liter desiccator (desiccator B) were separately connected to a vacuum pump. Desiccator B was disconnected and allowed to equilibrate with room air whilst desiccator A was evacuated to a pressure of 100 mmHg. Four male ICR albino mice (22-28 g) were placed in desiccator B. Desiccator B was then closed to room air and connected to desiccator A. The pressure inside desiccator B was monitored using a memory manometer and at the point were the pressure in desiccator B reached 200 mmHg (usually within 14 seconds), the two desiccators were disconnected from the vacuum pump and the pump switch off. The survival time from the moment of induction of hypoxia to the time of cessation of respiration was recorded for each mouse for a maximum of 15 minutes after which time room air was reintroduced to desiccator B. Survivors were monitored for signs of lethargy or vitality.

Effect of drug treatment was assessed as the percent of the survival time of the drug treated group with respect to the saline injected or vehicle injected control group. Control groups were run twice, before and after each experimental group and consisted of 8 mice in groups of 4 mice to ensure a constant residual volume of oxygen in all tests. The effect of each does of test drug was determined in duplicate i.e. two groups of 4 mice. The range of survival times of control mice was from 108-180 seconds.

Positive reference drugs were sodium pentobarbital at a dose of 40 mg/kg, and diazepam 10 mg/kg given 0.5 h prior to hypoxia, physostigmine 0.2 and 0.4 mg/kg and neostigmine 0.2 mg/kg given sc 30 min before hypoxia. Methyl atropine 1 mg/kg was given sc. 10 min. before physostigmine.

Test drugs were dissolved in 0.9% saline, and injected sc. in the nip of the neck at a dose in accordance with body weight, 60-90 min. before hypoxia. The volume of injection was 0.2-0.3 mL per mouse (10 mL/kg). The initial dose was about one third of the reported LD₅₀ for acetylcholine esterase inhibition. If no protection could be obtained, the dose was further increased to the nearest non-toxic dose. In case of protection, the dose was further reduced in an attempt to locate the “protective” dose range.

Per cent survival times as compared to saline treated control is shown in Table 14.

TABLE 14 Survival Time of Mice Having Experienced a Hypobaric Episode Time of dose (min Protection Dose before (% of Compound mg/kg hypoxia) control) p Control 100 (saline) Nembutal 40 30 253 ± 200 <0.005 Diazepam 10 30 316 ± 78  <0.003 Neostigmine 0.2 30 141 ± 32  <0.01 Physostigmine 0.2 30 453 ± 222 <0.001 0.4 30 552 ± 210 <0.001 Physostigmine 0.4 30 296 ± 193 <0.05 and 1.0 40 Atropine methyl nitrate  1 8 60 637 ± 116 0.007 4 60 470 ± 200 0.001 2 60 120 ± 51  NS 24 50 60 738 ± 00  <0.001 21 60 269 ± 166 <0.02 25 100 60 761 ± 91  0.001 75 60 559 ± 225 0.00 50 60 380 ± 231 0.01 25 60 84 ± 35 NS 27 50 60 455 ± 23  <0.001 3 60 287 ± 119 <0.00 15 60 143 ± 56  <0.05 8 60 119 ± 45  NS 29 77 60 508 ± 206 <0.001 51 60 638 ± 10  <0.001 25 60 131 ± 56  NS 25 30 273 ± 183 <0.02 10 50 90 705 ± 101 0.001 25 90 700 ± 201 0.001 10 90 304 ± 129 0.001 12 20 60 725 ± 128 <0.001 15 60 649 ± 221 <0.001 10 60 386 ± 238 <0.01 7 60 248 ± 97  <0.001

Example 5 Neurological score and brain infarct size in male Wistar rats after middle cerebral artery occlusion (MCA-O)

A modification of the procedure described by Tamura, et al was used (Tamura A, Graham D1, McCulloch J., Teasdale GH (1981) J. Cereb. Blood Flow and Metab. 1: 53-60). Male Wister rats (Olac England-Jerusalem) 300-400 g each were anesthetized with a solution of Equitesine administered i.p. at a dose of 3 ml/kg. Equitesine consists of 13.5 ml sodium pentothal solution (60 mg/ml), 3.5 g chloral hydrate, 1.75 g MgSO₄, 33 ml propylene glycol, 8.3 ml absolute alcohol, made up to 83 ml with distilled water.

Surgery was performed with the use of a high magnification operating microscope, model SMZ-2B, type 102 (Nikon, Japan) In order to expose the left middle cerebral artery, a cut was made in the temporal muscle. The tip of the coronoid process of mandible was excised as well and removed with a fine rongeur. Craniectomy was made with a dental drill at the junction between the median wall and the roof of the inferotemporal fossa.

The dura matter was opened carefully using a 27 gauge needle. The MCA was permanently occluded by microbipolar coagulation at low power setting, beginning 2-3 mm medial to the olfactory tract between its cortical branch to the rhinal cortex and the laterate striate arteries. After coagulation, the MCA was severed with microscissors and divided to ensure complete occlusion. Follow this, the temporalis muscle was sutured and laid over the craniectomy site. The skin was closed with a running 3-0 silk suture. A sham craniectomy operation was performed on a parallel group of rats, but without cauterization of the MCA.

During the entire surgical operation (20-25 min) group, body temperature was maintained at 37 to 38° C. by means of a body-temperature regulator (Kyoristsu, Japan) consisting of a self-regulating heating pad connected to a rectal thermistor. At 24 and 48 hours post surgery a neurological score was taken in order to assess the severity of the injury in the drug treated rats with respect to their untreated controls.

Drugs were administered as an s.c. injection, according to the following schedule:

Compound 24: 7.8 mg/kg 15 minutes prior to MCA-O and 6.5 mg/kg 2 hours post MCA-O.

Compound 25: 43 mg/kg 90 minutes prior to MCA-O and 30 mg/kg 3 hours post MCA-O.

After 48 hours of ischemia induced by permanent occlusion morphometric, the animals were anesthetized with Equitesine and measurement of infarct volume was performed as follows by TTC (2,3,5-triphenyl tetrazolium chloride) staining. TTC 1% in saline was prepared immediately before use and protected from exposure to light by aluminum foil wrap. MCA-O rats were deeply anesthetized and a 23-gauge butterfly needle with an extended tubing and a 20 ml syringe was inserted into the ventricle via thoracotomy. The right atrium was incised to allow outflow of saline. Heparine 50 i.u. in saline was delivered until the perfusate was bloodless. A 30-ml TTC-filled syringe was exchanged for the saline syringe and TTC was injected into the left ventricle at a rate of 5 ml/min. Both perfusate solutions were administered at 37.5° C. The brains were removed and immersed into 20 ml of 1% TTC contained in tightly closed glass vials. These were further placed for 2 hours in a water bath maintained at 37° C. The TTC solution was decanted, the brains removed, wiped dry and placed into 10% buffered formalin solution for 3 days. Six coronal slices each 2 mm, thick, 3,5,7,9,11 and 13 mm distal from the frontal pole were obtained with a brain matrix (Harvard Apparatus, South Natick, Mass.). Infarction areas were measured with a video imaging and analyzer from both sides of the coronal slices and expressed in mm². The volume of the infarcted region in mm³ was calculated by taking the sum of the ischemic areas in all six slices. The volume of infarcted region for the saline control and compounds 24 and 25 are given in Table 15 a.

Neurological score

The neurological score was measured in a manner slightly different from that given in Example 3. This method consists of the sum total of a series of ratings assigned to the performance of specific locomoter activities in a given rat. The scale runs from 0 (fully normal rats) to 13 (fully incapacitated rats). Most parameters are rated as either 0 (normal), or 1 (incapacitated) others are graded. The following tests were used in the present study:

General observation tests: hypoactivity, sedation, piloerection.

Motor reflex. Rats were lifted by the tail about 15 cm above the floor. Normal rats assume a posture in which they extend both forelimbs towards the floor and spread that hind limbs to the sides in a trapeze-like manner. MCAO, when severe, causes consistent flexion of the contralateral limb.

Motor ability. This is seen as the ability to grasp a rod 1 cm in diameter by the contralareral limb for 5-15 sec when the rat is left hanging on the rod through the arm pit.

Motor coordination. Normal rats are able to walk up and down a beam, 5 cm wide placed at a moderate slant. Failure to walk the beam in either direction reveals some motor incoordination, lack of balance and limb weakness.

Gait. Ability to restore normal position to either hind contralateral or fore contralateral limb when intentionally displaced while on a narrow beam.

Balance. Ability to grasp and balance on a narrow beam 2 cm wide.

Locomoter activity. Total movements over a period of 15 min in an automated activity cage.

Ratings assigned to each of the above parameters are given in Table 15.

TABLE 15 Neurological scoers assigned to each of 10 parameters of posture and locomotion Parameter Score a. Activity in home cage normal = 0 hypoactive = 1 b. Sedation none = 0 marked = 1 c. Piloerection none = 0 marked = 1 d. Extension of contra- good = 0 flexed limb = 1 lateral forelimb towards floor when lifted by tail e. Spread of contralateral good = 0 flexed limb = 1 hind limb when lifted by tails (trapezoid posture) f. Grasp rod with good = 0 poor = 1 contralateral limb for 5-15 sec. when suspended by armpit g. Walk on beam good = 0 poor = 1 5 cm wide h. Resoration of contra- good = 0 poor = 1 (one limb) lateral hind and/or     2 (two limbs) forelimb to original position when intentionally dis- placed i. Grasping & balance on good = 0 poor = 1 beam 2 cm wide j. Motor activity with  0-25% of control = 3 respect to control 26-50% of control = 2 (15 min in activity cage) 51-75% of control = 1 76-100% of control = 0 k. Tendency to lean on 1 contralateral side l. Contralateral circling 1 when pulled by tail m. Contralateral circling 1 spontaneous.

Table 15a shows the effect of compounds 24 and 25 in this model, comparing the change in NSS measured in 24 and 48 hours post injury.

TABLE 15a Compound ΔNSS* Volume infarction Mean ± SD mm⁻ Saline 0.745 211 ± 75 24 1.625 152 ± 45 25 1.78 189 ± 54 *Difference in ΔNSS measured at 24 hours and 48 hours. From this it can be seen that compounds 24 and 25 have a longer lasting effect than the saline treated control. 

What is claimed is:
 1. A compound of Formula I

wherein when a is 0, b is 1 or 2; when a is 1, b is 1, m is from 0-3, X is O or S, Y is halogeno, R₁ is hydrogen or C₁₋₄ alkyl, R₂ is hydrogen, C₁₋₄ alkyl, or optionally substituted propargyl and R₃ and R₄ are each independently hydrogen, C₁₋₈ alkyl, C₆₋₁₂ aryl, C₆₋₁₂ aralkyl or C₆₋₁₂ cycloalkyl each optionally substituted.
 2. A compound according to claim 1, wherein X is
 0. 3. A compound according to claim 1, wherein X is S.
 4. A compound according to claim 1, wherein a is 0 and b is
 1. 5. A compound according to claim 2, wherein a is 0 and b is
 1. 6. A compound according to claim 3, wherein a is 0 and b is
 1. 7. A compound according to claim 4, wherein R₂ is selected from the group consisting of hydrogen, methyl, ethyl or optionally substituted propargyl.
 8. A compound according to claim 5, wherein R₂ is selected from the group consisting of hydrogen, methyl, ethyl or optionally substituted propargyl.
 9. A compound according to claim 6, wherein R₂ is selected from the group consisting of hydrogen, methyl, ethyl and optionally substituted propargyl.
 10. A compound according to claim 7, wherein R₂ is propargyl.
 11. A compound according to claim 8, wherein R₂ is propargyl.
 12. A compound according to claim 9, wherein R₂ is propargyl.
 13. A compound according to claim 1, wherein one of R₃ or R₄ is methyl and the other is hydrogen, methyl, ethyl, butyl, propyl, hexyl, phenyl, benzyl, or cyclohexyl.
 14. A compound according to claim 2, wherein one of R₃ or R₄ is methyl and the other is hydrogen, methyl, ethyl, butyl, propyl, hexyl, phenyl, benzyl or cyclohexyl.
 15. A compound according to claim 3, wherein one of R₃ or R₄ is methyl and the other is hydrogen, methyl, ethyl, butyl, propyl, hexyl, phenyl, benzyl, or cyclohexyl.
 16. A compound according to claim 4, wherein one of R₃ or R₄ is methyl and the other is hydrogen, methyl, ethyl, butyl, propyl, hexyl, phenyl, benzyl, or cyclohexyl.
 17. A compound according to claim 5, wherein one of R₃ or R₄ is methyl and the other is hydrogen, methyl, ethyl, butyl, propyl, hexyl, phenyl, benzyl, or cyclohexyl.
 18. A compound according to claim 7, wherein one of R³ or R⁴ is methyl and the other is hydrogen, methyl, ethyl, butyl, propyl, hexyl, phenyl, benzyl, or cyclohexyl.
 19. A compound according to claim 10, wherein one of R₃ or R₄ is methyl and the other is hydrogen, methyl, ethyl, butyl, propyl, hexyl, phenyl, benzyl or cyclohexyl.
 20. A compound according to claim 13, wherein the group OC(X)NR₃R₄ is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon atom.
 21. A compound according to claim 14, wherein the group OC(X)NR₃R⁴ is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon atom.
 22. A compound according to claim 15, wherein the group OC(X)NR₃R₄ is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon atom.
 23. A compound according to claim 16, wherein the group OC(X)NR₃R₄ is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon atom.
 24. A compound according to claim 17, wherein the group OC(X)NR₃R₄ is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon atom.
 25. A compound according to claim 1, wherein the compound is an optically active enantiomer.
 26. A compound according to claim 2, wherein the compound is an optically active enantiomer.
 27. A compound according to claim 3, wherein the compound is an optically active enantiomer.
 28. A compound according to claim 4, wherein the compound is an optically active enantiomer.
 29. A compound, selected from the group consisting of: (rac) 6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (rac) 6-(N,N-dimethyl, carbamyloxy)-N′-methyl-N′-propargyl-1-aminoindan HCl; (rac) 6-(N-methyl, N-ethyl-carbamyloxy-N′-propargyl-1-aminotetralin HCl; (rac)6-(N,N-dimethyl-thiocarbamyloxy)-1-aminoindan HCl; (rac) 6-(N-propyl-carbamyloxy-N′-propargyl-1-aminoindan HCl; (rac) 5-chloro-6-(N-methyl, N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (S)-6-(N-methyl), N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; and (R)-6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan hemi-(L)-tartrate.
 30. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
 31. A method of treating a subject suffering from Alzheimer's disease or dementias which comprises administering to the subject an amount of the compound of claim 1 effective to treat Alzheimer's disease or dementias.
 32. The method of claim 31, wherein dementias include static dementia, Alzheimer's-type dementia, senile dementia, presenile dementia, progressive dementia, vascular dementia or Lewy body dementia.
 33. A method of treating a subject suffering from neurotrauma which comprises administering to the subject an amount of the compound of claim 1 effective to treat neurotrauma.
 34. A method of treating a subject suffering from memory disorder which comprises administering to the subject an amount of the compound of claim 1 effective to treat memory disorder.
 35. The compound of claim 1 having the structure:

and racemic mixtures, enantiomers, and salts thereof.
 36. The compound of claim 35 wherein the enantiomer is the R enantiomer.
 37. The compound of claim 35 wherein the enantiomer is the S enantiomer.
 38. The pharmaceutical composition comprising the compound of claim 35 and a pharmaceutically acceptable carrier.
 39. The pharmaceutical composition comprising the compound of claim 36 and a pharmaceutically acceptable carrier.
 40. The pharmaceutical composition comprising the compound of claim 37 and a pharmaceutically acceptable carrier. 